Asymmetric catalysis is an important area of chemistry, invaluable in the production of enantiomerically enriched products. The manufacture of pharmaceuticals and specialised chemical compounds are two particular industries where stereo-selective synthesis is often essential.
Hydrogenation reactions are used in a variety of synthetic methods and asymmetric control of hydrogenation has been well studied. In particular, catalysts for the asymmetric reduction of carbonyl and imino groups have been known for many years.
Ruthenium η-6 arene complexes were first reported as suitable catalysts for asymmetric hydrogenation by Noyori, and co-workers (S. Hashiguchi, A. Fujii, J. Takehara, T. Ikariya, R. Noyori, J. Am. Chem. Soc. 1995, vol 117, 7562-7563). These catalysts have been extensively tested and commercialised and are effective at the asymmetric reduction of ketones and imines to alcohols and amines respectively using a number of reducing agents.
Wills reported, in 2005, an improvement of the Noyori catalyst, which demonstrates increased reactivity on a wider range of substrates (A. M. Hayes, D. J. Morris, G. J. Clarkson and M. Wills, Am. Chem Soc, 2005, vol 127, 7318-7319). Wills catalysts, or so called ‘tethered’ catalysts, comprise a ligand having an η-6 arene group co-ordinated to a metal centre, wherein the arene group is also covalently linked to a second portion which co-ordinates to the remaining available positions around the metal centre.
Various synthetic routes have been proposed to make these complexes, many of which require multi-step reactions via a range of complex mechanisms. One such synthesis requires i) Birch reduction of an alcohol using an onerous combination of sodium metal and liquid ammonia, ii) conversion of the alcohol to an aldehyde using Swern oxidation, iii) reductive coupling of the aldehyde with the diamine component, iv) complexation of the product with ruthenium trichloride and v) conversion of the initially formed dimer to a monomer.
An alternative synthesis requires i) Birch reduction of an alcohol, ii) conversion of the alcohol to the tosylate, triflate, mesylate or related reagent, iii) coupling with the diamine component, iv) complexation of the product with ruthenium trichloride and v) conversion of the initially formed dimer to a monomer. Although some of these reactions can be ‘telescoped’ into a shorter practical sequence by performing the last two steps in a ‘one-pot’ process, many of these processes are undesirable.
Further, many of these reactions require the presence of a cyclodienyl intermediate in order for the η-6 arene ring to form and co-ordinate with the metal centre. This cyclodienyl intermediate limits the range of substituents that can be arranged around the arene ring as electron donating groups will cause aromatisation of the ring prior to co-ordination with the metal centre thereby preventing the desired complex from forming.
Various attempts have been made to synthesise these complexes using intramolecular ring swapping reactions such as M. Ito, H. Komatso, Y. Endo and T. Ikariya, Chem. Lett. 2009, 38, 98-99. However, there is no evidence that such approaches do not work with larger multidentate ligand counterparts
The invention is intended to overcome or ameliorate at least some of the problems outlined above.